The proposed research builds upon the background of knowledge on the chemistry of ribonucleases and deoxyribonucleases and their inhibitors, on the effects of administered nucleases on cell viability and virus multiplication, and on the preparation of derivatives of RNase that have enhanced enzymic activities of tissue-oriented cellular uptake. We will complete a thorough chemical characterization of the interaction of RNases of the pancreatic type and the pure RNase inhibitor that we have isolated from human placenta. Inhibitors from other tissues will be purified by affinity chromatography for comparative structural studies by chemical and immunological techniques. The cytoplasmic neutral RNAses normally found complexed to the inhibitor will be purified and characterized. The dimer of RNase formed by cross-linkage with dimethyl suberimidate has been subjected to reductive lactosylamination to give 7 carbohydrate residues per molecules; in initial tests, 70% of this radioactively labeled derivative with terminal galactosyl groups is taken up by the liver after intravenous injection in rats. Cooperative research is planned on the effect of the administration of this derivative and analogos to rats with liver tumors. The effects of coupling other carbohydrates to RNase on the specific uptake by different tissues will be determined. Polyspermine-RNase has been shown to be a derivative with marked new properties, which include a several hundered fold increase in the rate of hydrolysis of the double-stranded RNA of reovirus-3; derivatization of polyspermine-RNase will be undertaken to increase its retention in vivo. Means of minimizing the immunogenicity or RNase and DNase derivatives by chemical coatings will be tested. The studies of nucleases of different tissues will be extended through characterizations of two enzymes recently isolated in this laboratory from bovine brain, an exoribonuclease and 2',3-cyclic nucleotide 3'-phosphohydrolase, with the aim of broadening the understanding of the nucleases of this organ.